The Roles of Microtubules and Membrane Tension in Axonal Beading, Retraction, and Atrophy.

Axonal beading, or the formation of a series of swellings along the axon, and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here, we report controlled experiments that can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde, and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation, vis-à-vis beading or retraction. Elucidating the mechanisms of these shape transformations may facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.

Tamarind seed coat extract restores fluoride-induced hematological and biochemical alterations in rats.

Fluoride (F-) is becoming an ineluctable environmental pollutant causing deleterious effects in humans. In the present study, we examined whether tamarind seed coat extract (TSCE) is beneficial against the F--induced systemic toxicity and hematological changes. Wistar rats were randomly grouped as follows: group I served as control; group II intoxicated with sodium fluoride (NaF, 300 ppm) in drinking water; group III was administered through oral intubation with TSCE (100 mg/kg bw); group IV was treated with NaF (300 ppm) in association with TSCE (100 mg/kg bw) for 30 days. The results indicated that F- exposure induced oxidative stress as evidenced by elevated levels of reactive oxygen species and lipid peroxidation in the brain, liver, and kidney. F- administration modulates hematological indices-WBC, RBC, and mean corpuscular volume. Moreover, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acetylcholinesterase, and monoamine oxidase significantly increased on F- exposure. Conversely, δ-aminolevulinic acid dehydratase and glutathione/reduced glutathione ratio were decreased. Activity of antioxidants-superoxide dismutase, catalase, glutathione peroxidase, and vitamin C-was also significantly decreased due to F- administration. Treatment with TSCE effectively mitigated the alterations through its antioxidant potential. The data suggested that the TSCE had beneficial effects in alleviating the F--induced toxicity and hence can serve as a promising neutraceutical agent.

Protocatechuic acid methyl ester modulates fluoride induced pulmonary toxicity in rats.

We have found that protocatechuic acid methyl ester (PCAME) attenuates fluoride (F-) toxicity in lung epithelial cells (A549). However, this finding has to be confirmed with in vivo studies. Further, the effect of PCAME on F- induced pulmonary fibrosis and inflammation remains limited. Hence, the present study is aimed to determine the protective effect of PCAME against F- induced pulmonary toxicity in female albino Wistar rats. The animals were treated with sodium fluoride (NaF, 300 ppm in drinking water ad libitum) alone or in combination with PCAME (25 or 50 mg/kg bw/day by oral intubation) for 60 days and analyzed for changes in lung histology, oxidative stress, inflammation, apoptosis and fibrosis markers. PCAME supplementation prevented the F- induced changes in the above markers. Also, altered serum and bronchoalveolar lavage fluid markers and lung histoarchitecture were also restored by PCAME. F- induced modulations in oxidative stress markers, TUNEL positive cells and mRNA levels of inflammatory genes further normalized by PCAME in lung tissues. These results revealed that PCAME effectively attenuated the F- induced changes in the rat lungs by reducing cellular F- accumulation and enhancing antioxidants level. Thus PCAME can be used as a nutraceutical agent for F- toxicity.

Possible Modulatory Effect of Tamarind Seed Coat Extract on Fluoride-Induced Pulmonary Inflammation and Fibrosis in Rats.

Fluorosis (fluoride toxicity) seems to be reduced by plant secondary metabolites. Tamarind seed coat extract (TSCE), a mixture of procyanidins and polyphenols, possesses numerous pharmacological activities. Regardless of its beneficial properties, the underlying molecular mechanism against chronic fluorosis in vivo is not known. Hence, the present study is aimed to investigate the efficacy of TSCE against fluoride (F-)-induced pulmonary toxicity in rats. Female Wistar rats were randomly divided into four groups and treated with NaF (300 ppm in drinking water) and TSCE (100 mg/kg/bw by oral intubation) alone and in combination daily for 30 days. The results showed that F- exposure-induced modifications in lung injury markers in both serum and BALF were restored by TSCE supplementation. Additionally, F--induced changes in oxidative stress (NOX4 and p38α MAPK), inflammation (NF-κB, COX-2, and HO-1), apoptosis (Hsp27, Hsp60, caspase3p20, and PARP1), and fibrosis (TGF-ß1, psmad3, Col1αl, and hydroxyproline level) markers in the lungs were modulated by TSCE. Thus, TSCE offers protection against F--induced pulmonary inflammation and fibrosis in rats.

Pulmonary fluorosis: a review.

The increased industrialization and improvised human lifestyle lead to a surge in environmental pollution nowadays. Even the chemicals which are known as prophylactic agents were currently liable to be toxic. One among them is inorganic fluoride whose wider application in numerous processes makes it as an inevitable environmental contaminant and industrial pollutant. Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity. Hence, we have focused on the molecular mechanism of action of fluoride compounds on pulmonary system. A study of literatures that focused on the potential physiological and toxicological consequences of fluoride on pulmonary system was carried out. The goal of this review is to present an overview of the research carried out till date on the molecular aspects of fluoride exposure with emphasis on pulmonary system and their possible mechanisms.

Protocatechuic acid methyl ester ameliorates fluoride toxicity in A549 cells.

The present study is aimed to determine the potential benefits of protocatechuic acid methyl ester (PCAME) against fluoride (F-) induced lung toxicity using A549 cells. The cells were treated with sodium fluoride (NaF) alone and in combination with PCAME for different time points (0-24 h) and evaluated for intracellular reactive oxygen species (ROS) production, F- content, oxidative stress markers, apoptosis and mRNA expression of redox signaling and inflammatory genes. The results shown that PCAME alleviates the toxic effects of F-via modulating its bioavailability, intracellular calcium level, mitochondrial membrane integrity and redox signaling in A549 cells. F- induced changes in ROS generation, oxidative stress markers, TUNEL positive cells and mRNA levels of inflammatory genes were further normalized by PCAME. Taken together, these findings revealed that PCAME effectively attenuated the F- induced changes in oxidative stress, inflammation and apoptosis markers by reducing its cellular content, ROS generation and biochemical and molecular changes. Thus PCAME can be used as a nutraceutical agent for F- toxicity.

Tamarind seed coat ameliorates fluoride induced cytotoxicity, oxidative stress, mitochondrial dysfunction and apoptosis in A549 cells.

Fluoride (F) is an environmental contaminant and industrial pollutant. Molecular mechanisms remain unclear in F induced pulmonary toxicity even after numerous studies. Tamarind fruits act as defluoridating agents, but no study was conducted in in vitro systems. Hence, we aimed to assess the ameliorative impact of the tamarind seed coat extract (TSCE) against F toxicity utilizing lung epithelial cells, A549. Cells were exposed to sodium fluoride (NaF-5 mM) alone and in combination with TSCE (750 ng/ml) or Vitamin C (positive control) for 24 h and analyzed for F content, intracellular calcium ([Ca(2+)]i) level, oxidative stress, mitochondrial integrity and apoptotic markers. TSCE treatment prevented the F induced alterations in [Ca(2+)]i overload, F content, oxidant (reactive oxygen species generation, lipid peroxidation, protein carbonyl content and nitric oxide) and antioxidant (superoxide dismutase, catalase, glutathione peroxidase and glutathione) parameters. Further, TSCE modulates F activated changes in mitochondrial membrane potential, permeability transition pore opening, cytochrome-C release, Bax/Bcl-2 ratio, caspase-3 and PARP-1 expressions. In conclusion, our study demonstrated that TSCE as a potential protective agent against F toxicity, which can be utilized as a neutraceutical.

Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats.

Several studies have shown that acute fluoride (F(-)) exposure impairs cardiac function, but the molecular mechanism is not clear. In order to study this, male Wistar rats were treated with single oral doses of 45 and 90 mg/kg F(-) for 24 h. A significant accumulation of F(-) was found in the serum and myocardium of experimental rats. F(-) treatment causes myocardial necrosis as evident from increased levels of myocardial troponin I, creatine kinase, lactate dehydrogenase and aspartate transaminase. In addition, F(-) induces myocardial oxidative stress via increased reactive oxygen species, lipid peroxidation, protein carbonyl content and nitrate levels along with decreased in the levels of enzymatic (superoxide dismutase 2, catalase, glutathione peroxidase and glutathione s transferase pi class) and non-enzymatic (reduced glutathione) antioxidants. Notably, F(-) triggers myocardial apoptosis through altered Bax/Bcl2 ratio and increased cytochrome c, caspase 3p20 and terminal deoxynucleotidyl transferase dUTP nick end labeled positive cells. An increased cardiac expression of Nox4 and p38α MAPK in F(-) treated rats indicates the oxidative and apoptotic damage. Moreover, ultra-structural changes, histopathological and luxol fast blue staining demonstrates the degree of myocardial damage at subcellular level. Taken together, these findings reveal that acute F(-) exposure causes cardiac impairment by altering the expression of oxidative stress, apoptosis and necrotic markers.

Caffeic acid, a phyto polyphenol mitigates fluoride induced hepatotoxicity in rats: A possible mechanism.

Fluoride induced hepatotoxicity has been extensively studied in both humans and animals. However, the mechanism underlying in the hepatotoxicity of experimental fluorosis remains obscure. The severity of fluoride toxicity was reduced by oral administration of certain plant derived antioxidants. Caffeic acid (CA) a polyphenolic compound has diverse range of pharmacological activity in the biological system. Therefore, the present study was aimed to investigate the protective mechanism of CA, against fluoride induced hepatotoxicity in rats. The rats were treated with 300 ppm of NaF via drinking water ad libitum alone and in combination with CA at a dose of 50 mg/kg daily for 30 days by oral intubation. CA treatment significantly prevented fluoride induced hepatic damage as evident from the histopathological studies and declined levels of serum fluoride and liver marker enzymes. A significant decrease in the levels of enzymatic (SOD2, CAT, GPx, and GSTpi class) and nonenzymatic (GSH and Vitamin C) antioxidants along with increased ROS, lipid peroxidation, protein carbonyl content, and nitrate levels by fluoride were also prevented in these groups. In addition, CA inhibits fluoride induced apoptosis by altering the Bax and caspase-3p20 expressions. Further, fluoride induced upregulation of Nox4, p38α MAPK, Hsp60, and downregulation of Hsp27 are the indicators for the detection of oxidative damage, apoptosis, and mitochondrial stress was also modulated by CA. These findings reveal that CA supplementation has a protective effect against fluoride induced hepatotoxicity in rats.